Process of producing cyanine dyes



Paul Nawiask speeryLuf "iline &Fi

' I NO Dr l, a 1 4 Cla ims. The present invention relates to'th of trimethine cyaninedyesta-nd parti in which the carbon atom in the meso position of *the trime'thine *chain is 'monosubstitut alkylor mono-cyclic aryl'radical.

lt 'isl' propose'd "in U. S. P.**2,1:07,3'l9"to-produce trimethine cyanine dyes in rwhichthe meso car- Jbon-iatomt of the trimethenyl' chainfis.- substituted zby amalkylsor aryl radical by reacting a cycloammonium quaternary saltsofr the type usuahin ,the rormation-ofi;cyanineitdyesrwith an alkyl ester of 1a ithioimide -.'i11 Whihl' substituted by ea; phenyl: radical which may contain a methyl ornnitrosubstituent. 'Iheoprocess of the patent operates smoothly to produce the desiredproductstin fairly good yields e'production cularly those to obtain high yieldstoi cyaninedyes by the usual methods, *Inmmany casesthe yields obtained in commercial processes amount to as little as per cent. lt is a rare case indeed whenthe yields obtained approachthose of 'theoryr Yields-which are as F high as 50 'per' centfi moreover, are the exceptionrathefithan r we have mow fcrun'd that the "yields *of trimethine' 'cyanine 'dyes containing a substituent ,slea nj be: thioimide utilized. for -reaction with the oycloam- 'monium' quaterriary *salt i is one -in vwhich the iahenyl raidical attached to the' nitrogen atom of the thioimide is substituted in para-positiozibya halogen atom. The particular reason Why improved yields are obtained when u eoftthis character is unknown. spite any theory involved, the ,bytusingroun thioimides weeobtain yields which are far superior to any that can be obtained when working-according-toatheppatent.

I t 1,; It- :is accordingly an object oil-our invention to produce ,tri-methine t-cyan ines the, imeso carbon atom f the:trirnetheny1 chain ;oiwh.ichis substi tuted byrreactingaa ycloammonium quater ary =-salt with an; ,alkylestergof a rphenylated i thioimide in which the phenyl: radical issubstitutedin pai-aposition to the nitrogen atom by a halogen atom. It is a, further object of theinvention-to produce trimethinerya ninedyes the meso carbon atom of the trimethenyl chain of whichis substituted by reacting-inthe abs agent, a: cycloarnmonium qu alkyl ester of a phenylated thioimide in which thetphenyl radical is substituted in'para-position to t/he. nitrogen atom *by' a -halogen atoni and to further react the intermediate thereby produced *with another cycloammoiriuni; quaternary salt.

I t is'a furtherobjectdf thetinventiontoprovide afprocess' which produces higher yields of trif'methine cyaniriesrtham'has' 'beenf heretofore tpossfi'ble; by using in lieu .of the usual alkyl esters'i of I :an we awing. ApplicationJu l Serial ed by an the tnitrogen natom .wiS

It mustbe remembered, howeyer,-that it is a diflicult matter on the meso -c'arbon" atomrofi the trimethine chain greatly improved "if the *alkyl ester of the singqthioimides i 1- t i i t tin-which R istalkyl, suchas .methy1,,ethyl,,propyl, fact remains that ence of'aco-ndensihg aternary salt with an i l i r p QQFH PnooEss oF rnonUoINelmrEs it i y, Summit, N.,J., andRobertJames kin, Tex.,

1m Corporation t corporation ofuDelaware phenylatedlthioimidestthose in w ich the that para .tol'the. nitrogen atom radicalnis substituted b halogen. H

Otherj further. 1 objects or, theejinvention 5 pearfastthe description proceeds.

1 "The;cycloammoniuml,quaternary salts which i alkyl I --wherein X represents the atoms cnecessaryto grouplsuch as iodine;zch'lorine;merchlorategpara toluene-sulfate andttherlike,:zand :l1alky1-ur1eans ethyl; methyl, .ipropyl;.1butyl-iiand the; like. EXamples of such'compounds are 2-methyl-benzthi- :azole ralkiddide, 2emethylf-tbenzselenazole talkiedide;f2-*methylsbenzoxazole alkiodide, .2e-methyl- .tpyridine alkiddid'axqumaldine:alkiodide, r2+methyl indolenine alkio'dide;fzlemethylethiazoline alkiodide, 2-methyl-se1enazole alkiodide, lepidine alkiodide, and the like. t The thioimides which are: :utilized -for:- reaction with said cycloammon' .butyl; stearyl, andttheilike orlaryl such as ,phenyl, chlorophenyl, i hmethylphenyl, t imethoxyphenyl, Qethoxyphenyl; aminophenyl and the like, and mu tis halogen. r'Ihealkyl radical attachedito'. the sul- 40 fur atom may be methyl, ethyl 'hexyl, decyl stearyl or the like. 'It" is tobe ob? served that the a phenyl radical attached ,to the nitrogen atom bears as the only substituent the halogen .atom in para-position to the nitrogen -1 atom. it has been found that'iilfsubstituents are presentin ortho-position, the reaction is blocked. On,the:.other. hand, substituents in meta-position t n'dency' to interfere to the nitrogen atom-have a te with the reaction. Jo

stages, the first involvingthefreaction"between the cycloammonium quaternarysa'ltfand thethioi imide :wvith s the formation :iof f the aanilino :.vinyl J5 tion of said intermediate with another cycloammonium quaternarysa1t-whichmaybe the same or different from that used in* producing the intermediate. It-is preferable to use about equimolecular proportions of the cycloammonium quaternary saltand thethioimide and equimolecmap.

completewa heterocyclic' nucleus lofithe: typeisusual in -cyanine=dyes, anion rneansca rsaltef-orming ium quaternarys'alts? have tiplropy utrl,

Thereaction is generallylcarried "out in two ular proportions of. the intermediateand the other cycloammonium quaternary salt.= If the cycloammonium quaternary salt is used in an amount in excess of the thioimide, some sym- I mediate and the other cycloammonium quaternary salt. Such condensing agents should be basic in character.

amme, tripropylamine, triethanolamine, dibutylamineQ dimethylaniline, N-methyl piperidine,

piperidine, and the like. It is to be pointed out, however, that condensing agents if employed in the preparation of theintermediate have'a detrimental effect on the reaction. It istherefore advisable to avoid the use of such condensing agents when reacting the cycloammonium quaternary salt with the thioimide. It will be observedthat in this respect the reaction also differs from that of the afore-mentioned patent, which suggests the use of acetic anhydride or pyridine in the production of the intermediates thereof.

The reaction between the cycloammonium quaternary salt and the alkyl ester of the 'phenylated thioimide is generally efiected by heating. The temperature may range from about 100 to about 200 C., but the-preferred temperature is in the neighborhood of-145 to 150 C. Generally lower temperatures are used in the second stage. A

The invention is illustrated by the following examples, in which the parts are by weight. It is to be understood, however, that the examples are illustrative and not limitative.

' Example 1 parts of 2-methylr-5-methoxybenzoxazole ethiodide and r 1 v T 10 parts of ethyl iso-thio-( l-chloropropionanilide) were heated together to about 148 to 150 C. for 2 hours, and the mixture cooled to 100 to 110 C.

Condensing agents which I have found to be suitable are pyridine, triethyl- Methanol was then added to'the mixture, the I same was chilled over night, filtered and washed with ether- There were thus obtained 8.8 parts of orange needles meltingat 209 C., representing a yieldof about 47.5 per cent of theory. The product thus obtained has the following structural formula:

I 0513s I 5 parts of 2.6-dimethylbenzthiazole ethiodide and 5 parts of the above-mentioned product were then reacted in 1 30 cc. of pyridine. I

light absorption of this compound is at 540 to 560 mu. The product, which is [3-ethy16-methyl-benzthiazole- (2) [3-ethyl-6 methoxy benzoxazole (2)] beta ethyl trimethinecyanine iodide, has the following structural formula:

The procedure was repeated while using a thioimide in which the phenyl radical attached to the nitrogen atom was unsubstituted. In this case, the yield of the intermediate was 20 per cent of theory and the yield of the trimethine cyanine, 13.3 per cent of theory. x 1

Example 2 5 parts of, 2.fi-dimethylbenzthiazole ethiodide were reacted with 1 5 parts of the intermediate of Example-.3 in 30 cc. of pyridine. Y I I 1 q A product was obtained in the form of dark green crystals melting at 237 C. in a yield'of about 52.4 per cent of theory.- Theproduct hasan'absorptionmaximum at 560 to 580 mu. Thepr'oduct, which is bis[3-ethyl-6-methyl-benzthiatole- (2)l-beta-ethyl-trimethine cyanine iodide, has the following structural formula: 1 i

' yThe 'procedurewas repeated while usingj an intermediate derived from a thioimide in which the phenyl radical attached to thenitrogen atom is unsubstituted and wherein said phenyl radical is substituted in'the para-positionto said nitrogen atom by a methyl group on the one hand and by a nitro group on the other hand. The yield in. the first instance was 27.7 per cent of. theory and in the second instance, 15.2 per. cent. of. theory and in the third instance, -.1 4.'Z 'per centiof theory. I l/ mmp fir I CtHa I The procedure was repeated while using the same thioimide, except that the phenyl radical attached to the nitrogen atom was unsubstituted in one case, was substituted in the para-position by methyl in another case, and in the para-position by nitro in the third case.. The yield .in the first case was 48 per cent of theory, in the second case 38,per cent of theory, and inthe third case 12 per cent of theory.

aavegee are slowly added. The mixturewas refluxed-for a about 1 /2 hours and after cooling therewas i added thereto t :1 part of potassium iodide in I 1part* of distilled water.

30*-cc.of ethyl acetate were then added' and 1 the mixture 'chilledxfiltered and washed withdistilled water and :ethyl acetate.

Ihe Dioductwas crystallized from 95 per cent pyridine by precipitationwith ethyl acetate. It

wasin theform of lustrous green crystals melting ati227PCWand was obtained in, a yield of about 35 to 40 per cent of theory. Theproduct when 3 incorporated in gelatin absorbed light waves in the range of 650to 660 mu. The product;

which is [3-ethyl-6-methyl-benzthiazo1ee(2) -[3- ethyl fi methoxybenzselenazole- (2) i beta ethyltrimethinecyanine iodide; the following structural f formula:

This iprocedure was repeatedwhile using: an in! termediate obtained fromthesame thioimide, except thatthe phenyl radical attached to the nitrogen atom thereof wasunsubstitutedu The trimixture was worked up methine cyaninethus obtainedrwas. producedpin a yield! of about 18:8: per cent l of theory:

y Example 5 20 partsof Z-methylbenzothiazole ethiodicle and 20vparts of ethyl iso-thio-(4-chloropropionanilide) were: heated :for 2 hoursatv about148ato 150 C. in an open flask. The mixture cooled to about 100 to 105 C. and t cc. oftmethanol were added thereto. After stirringfor about: with an ice-salt mixture for about 3hours, filtered and washed twice with-ether. 23.5 parts of the product were obtained in the form of red crystalsmelting atl'225f C. t t i i Exampladl 2O 1 parts of zv-methyle5emethoxybenzselenazole ethiodide were charged into a reactor equipped with a reflux" condenser containing 120-cc. of pyridine.

was then hour; the mixture is cooled The mixture was refluxed for 15minutes and there was added thereto overa period-of 1 hour 20 parts of the intermediate of Example 5.

The mixture is then heated under refluxior hours, cooled/to room temperature, "and poured into asolutionof '4 paits of potassium iodide. and

601cc. or water. The mixture is thenwell shaken andlpoured into 120cc. of ethyl acetate. The mixture was refrigerated ,for 24 hours, then. filterede The solid :product retainedwby thefil ter was washed 5 times with water, 5 times with ethyl acetate, 3/times with ether, after which it was dried "over barium chloride. 21:3.parts of .green crystalsamelting; at 195 to 200 .C. were obtained. 'I'he product was purified bytcrystalliza-t tion from methanol and a small amount of pyridine. The dye thus obtained =wasain the form intermediates derived from t 3 o1" green crystals: melting; at 114M142? C." The yield was per cent ottheory: l i a The procedure was twice repeated while using the -same thioimide; except that in one case the phenyl radical attached to the nitrogen atomthereof was unsubstituted and in the other case was substituted in the para-position by-a methyl radical The yield in the first instance was 24 per cent-of-"theofy andin thine: second case, 16.3per cent of theory. Example 7 4.54 parts er ethyl iso-thio- (q-bromopropionr anilideland l 5.07; parts of z-methylbenzselenaz oler ethe 8.76partsof the above. productand i n 8,16 parts {of 2-methylbenzselenazole ethiodide were refluxedt withfifl' ce. of pyfldineandth'e V in the manner described in Example 6 The dye wasjobtainecl in theforin of green crystals melting at 2102l1 C. in afyield a of 45.8'per cent of theory. The productjwhich is bis-[3-ethyl benz selenazole-(2) l beta -ethyltrimethinecyanine iodide, has the following structural formula: l

The procedure was repeated threetimes-while using the "same thioimide; except that-thephenyI radical attached tothe nitrogen atomin the first instance was unsubstituted and inthe second instance was substituted in the para-posh tion by methyl and in the third instancesin the para-positionaby nitrol In. the first;.case,-the yield of trimethine cyanine dyestuif was'2fir2rper the third case; 21,7 per cent of theory, 1

t x Emamble8 4154'- parts offlethylr isoethiow-bromoprm Dionanilide) and it i l 4318 partsof. 2rmethylefi-methoxybenzom azole ethiodide v v i V I were-'reactedin the manner described inExamp'le I; There were thus obtained 2.16% parts of atan powder having a. melting point of 210 to 2122C. and the following structure:

cent, inthesecond case, 25.4 per cent, andrin iodide The it 4- were refluxed with 10 cc. ofpyridine and worked up in the manner described. in Example 6. The dyestufi; which is identical with that of Exampie 1,- is obtained in a yield of 21.2 per cent of theory. .4 1

--Ea:amp lc'9' 5 -.parts of ethyl "iso-thioe (4-chloropropion- .anilidel and t t5 parts .of 2.5.6-trimethylbenzoxazole ethiodide r v were heated for 2 hours at 145-l50 C, After working up-the reactionmixture as described in Example 1, there were obtained 3.9 parts of a productin the formof orange-crystals melting at about 200C. The product had the following structural formula': 1 a

. with 3.1 parts of 2-methylbenzothiazo1e ethiodide in pyridine and the reaction mixture was workedup as described in Example 1. The dyestufi in the form ofblue-green crystals melting at 170 Crwasobt ained in a yield of 32 per cent oftheory. The dyestufi, whichfis, [3-ethyl 5.6-dimethyl-benzoxazole-(2)] [3-ethy1 .benz thiazole -.(2) -,betaethyl-trimethinecyanineIiodide, has the iollow ing structural formula: I

The procedure was repeated while utilizing the same thioimide except that the phenyl radical attached to the nitrogen atomthereof is unsubstituted... The: dyestuff in this case was obtained inayield-of only 9 .per cent of theory.

I Example 10 -Amixtureof 10 partsbf 2.6-dimethy1benzothiazo1e ethiodide and I 9.4parts of ethyl iso-thio-(4-chloroacetanilide)was heated at 148-150" C. for 2 hours 'while stirring. The mixture was cooled to 110 C. and cc. of methanol were thereupon added. The mixture was refrigerated over night and filtered. The solid residue was H of ether. The product in the form of tan crystals having a melting point of 263-264? C. was obtained in a, yield of about 65 per cent of theory.

The product had the following structural formula:

repeated while using the same thioimide except that the phenyl radical attached to the nitrogen atom thereof was unsubstituted. The yield was 49.5 per cent of theory.

The procedure was washed twice with 10 cc.

Example v11 l5 parts of 2 methyl-S-methoxybenzselenazole ethiodide were mixed with 30 cc. of pyridine, and the mixture heated to reflux.

4.85 parts of the product of Example 10 were slowly addedand the mixture refluxed for 1% hours. After cooling the mixture,.l .part of po-. tassium iodide in 1 part of distilled water, was added. 30 cc. of ethyl acetate were then incor porated in themixture andthe same was chilled and filtered. The filtered product obtained was washed with distilled water, ethyl acetate-and ether and recrystallized-from 10 parts of per cent pyridineby precipitation withnlO. per cent of ethyl acetate. The. product in the, form or lustrous dark blue crystals melting at 244 was obtained in a yield of '75 per cent of theory- The product, which] is. [B ethyLG-methyI-hBnzthi azole- (2).]; [3-ethyl-6-methoxy benzselenaz ole (2)lbeta-rnethyl-trimethinecyanine iodide, has the following. structural formula:

The procedure was repeated while utilizing the intermediate of Example 10 prepared with a thioimide in which the phenyl radical attached to the nitrogen atom is unsubstituted. 'In this case, the

yield of dyestuff was only 45'per cent of theory;

CHKO n 7 CH3 Ammo-ringer a ,1 are The procedure was repeated while utilizing the same thioimide except that the phenyl radical attached to the nitrogen atom wasunsubstituted. The yield of intermediate obtained was only 48 per cent of theory. k 1

5 parts of 2.6-dimethy1benzothiazole. ethiodide and I 6 .23 partsof the product of the above formula were refluxed-with pyridine'and worked up as in Example 11.. The product was recrystallized from 20 parts of 95 per cent pyridine. Thedyestufi in the, form of lustrous purple crystals melting at 241-242 C. was obtained in a yield of 26.9 per cent of theory, The product, which isf [3'-ethyl- 6-methyl-benzthiazo1e-(2) ]-[3ethyl 6 methoxy-benzoxazole-(2llbeta-methyl trimethinecyali ine iodide, has the following. structural form a:

with 9.4 parts-of ethyl iso-v theory;

then added to the reaction Eramplc 1 3 20 parts bf 2-methylbenzthiazole ethiodide I and: p

19.65 parts. of ethyl iso-thionp-chloroace tanilide) V were, mixed. and theurnixture was. heatedifor 2 hoursltat. 148-150; C. l The mixture'was then workedup as in Example 11 to a darkred powder meltingat 227;228? C. The yield was. 65 per cent of theory. Theprodu'ct hadthe followinglstruc tural formulay. p s

yieldof-intermediate was 58 parts of 2-.methylbenzselenazoleethiodide parts of 2-methylbenzothia.zole--ethiodidewere f'refluxedwith 60*ccw of'pyridine and' to the mixturetherewere added 1 11.7" parts "of; the above intermediate; The

product "after isolation from thereaction mixture wasrecrysta1liZed-from-methanol. Itwas obtamedin the form of "copper-colored plates in a 1 dide, has the following structural which is bis-t3 ethyl-benzthiazole-(2)l betamethyl trimethinecyanine iodide,- has the-fol1ow ingstructuralformulae I Y CzHs When proceeding 1 in. exactly the same .blll'; while utilizingeathioimideuin 'whichl the phenyl radical.

attached to? the. nitrogen: atom i unsubstituted, the eyie'ldr of the :dyestufi is .only 28 L percent of U V Emamplelda 3 part5 of-=2.fi dimethylbenzthiazoleethiodide A were-refluxed with '18 CG,0fpy lidille. There were mixture 3;5. parts of. the intermediatedescribedtin Example 10. The reactionmiixture Maslthemprocessed in the manner outlined in Example 11. The dyestuff was obtained in the form of lustrous purple needles melting at 283 C. in a yield of 38.5 per cent of theory. The dyestufi, which is bis-[3-ethyl-6- methyl benzthiazole (2)] beta methyl trimethinecyanine iodide, has the following constitution:

mo s -CH;

--CH=JZ While utilizing an intermediateprepared from a thioimide in which thephenyl radicaliattached to the nitrogen atom is unsubstituted, the yield of the dyestuff obtained is only 29.4 per cent of theory.

Example 10 parts of Z-methylbenzselenazole ethiodide were mixed with 8.45 parts of ethyl iso-thio-(p-chloroacetanilide) and the mixture was heated at 148M150 C.

for 2 hours. The mixture was then worked up in the manner described in Example 10. The

product in the form of brown crystals melting at 259-260 C.'was obtained in a yield of 79 per cent thio- (p chloroacetanilide) tained in the form of of theory. The product hadfthe followingstructuralformulaz, j H p By proceeding .in the-same mannepwhile utie lizinga thioimide in which the phenyl radical-attached to the nitrogen atom is unsubstituted,.the.

per. cent of theory.

werereactedwith. H

4.6]...pa1tscf the intermediate of the above structural formulain the mannerdisclosedrin Example ll. The prqduct a fter recrystallization, from 15 parts of 95 per cent pyridine, was obgreen needles melting at 284 C. The yield was The dyestuff, which is bis- [3-ethyl-benzselenazole- (2) ]-beta H5 Similar results are obtained when the ethyl isop is replaced by' anequivalent" amount for ethyl isonthj (rm-$311010A ben ylanilide); v a v Emmet I 2.74parlts of quinaldinesethiodide and 3.3 parts of the intermediate depicted by structural formula in Example 10 were refluxed with was in the form of dark 20 cc. ofpyridine for 1 hours.

- 20 cc. of ethylacetate were 'iadded, the mixture chilled and filtered. The solid after recrystallization from 10 parts of 95. per cent pyridine was 58 per cent of theoryr The product, which is l3i-ethyl-quinoline- (2)] [3-ethyl benzthiazole- (2fl beta methyl-trimethinecyanine-' iodidex has the following structural formula:

X the following formula:

in which X represents the atoms necessary to complete a heterocyclic nitrogenous ring system 2 per cent of theory.

of the type'usual in cyanine dyes with a compound of the following structural formula:

V al kyl anion in which X represents the atoms necessary to complete a heterocyclic nitrogenous ring system of the type usual in cyanine dyes with a product of the following formula:

in which hal is halogen and R is a member of the class consisting of alkyl and mono-cyclic aryl radicals, and further heating the intermediate so obtained with a cycloammonium quaternary salt of the following formula:

anion in which X has the value given above. v

4. The process as defined in claim 3 wherein the last-named cycloammonium quaternary salt is different from the first-named cycloammonium quaternary salt.

5. The process as definedin claim 1 wherein hal is chlorine, y

6. The process as defined in claim ii twherein hal is chlorine. '7. The process as defined in c1aim.3. wherein the first reaction takes place in the absence of a condensing agent and the second reaction takes 7 place in the presence of a basic condensing agent; 8. The process as defined inclaim 1 wherein the reaction is effected by heating'to' a temper-j ature ranging between to 200 9. The process as defined in claim the reaction is effected by heating to a temperature of about C.

10. The process as defined in claim 3 wherein the first reaction is effected by heating to a temperature of from about 125 to about 200 C. and the second reaction is effected-while refluxing the reaction mixture.

11. The process as defined in claim 1 wherein the cycloammonium quaternary salt and the thioimide are used in equimolecular proportions.

. 12. The process of producing [3-ethyl-6-methyl benzthiazol-(2) l-[B-ethyl-G-methoxy benzoxazole- (2) l-beta-ethyl-trimethine-cyanine iodide whichcomprises heating 2-methyl-5-meth-r oxy-benzoxazole ethiodide with ethyl iso-thio-(i chloropropionanilide) and heating the intermediate thus obtained with 2.6-dimethyl'benzthiazole ethiodide in the presence of pyridine.

13. The process of producing [3-ethyl-6-meth-. yl benzthiazole-(Z) l-[3-ethyl-6-methoxy-benzselenazole- (2) l -beta-ethyl-trimethinecyanine iodide which comprises heating 2.6-dimethyl benzthiazole ethiodide with ethyl iso-thio-(i-chloropropionanilide) and further heating the resulting product with 2-ethyl-5-methoxy-benzse1ena zole ethiodide in the presence of pyridine.

14. The process of producing bis-[3-ethyl-6-n methyl-benzthiazole-(2) l-beta-methyl trimethinecyanine iodide which comprises heating 2- methyl-benzthiazole ethiodide with ethyl iso-thio- (p-chloroacetanilide) and further heating the resulting product with 2.6-dimethy1 benzthiazol ethiodide in the presence of pyridine.-

, PAUL NAWIASKY. 1. 1

ROBERT J AMES' SPEER.

1 V wherein Certificate of Correction Patent No. 2,378,783. June 19, 1945.

- PAUL NAWIASKY ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Page 3, first column, line 28, Example 4, for that portion of the formula reading OOH read OOH page 6, second column, line 37, claim 13, for Z-ethyl read Z-methyl; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of case in the Patent Ofiice.

Signed and sealed this 24th day of June, A. D. 194:7.

LESLIE FRAZER,

First Assistant C'ommissioner of Patents. 

